Age-related macular degeneration (AMD) is a leading cause of blindness worldwide, affecting ageing populations. It has been estimated that 80 million people will be affected by AMD by 2020. The prevalence is 10% in patients 66 to 74 years of age that increases to 30% in patients 75 to 85 years of age. AMD is a degenerative disease characterized by progressive impairment of the macula, located near to the center of retina. Macula is the most concentrated region in photoreceptors and is therefore involved in central vision and visual acuity. There are risk factors associated with AMD, older age being the major one. Others consist in ocular factors (darker iris pigmentation, previous cataract surgery, hyperopic refraction) or systemic factors (cigarette smoking, obesity, diet, race, retinal stress (sunlight exposure) and cardiovascular diseases). Several genetic loci have been associated with AMD, including elements of the complement system such as CFH, the ARMS2/HTRA1 locus, C2, CFB, C3 and CF1. Genes of the HDL cholesterol pathway (LIPC, CETP and possibly ABCA1 and LDL), the LDL pathway (possibly APOE), the extracellular matrix (COL10A1, COL8A1, TIMP3), Glial Fibrillary Acidic Protein (GFAP) and the angiogenesis pathway (VEGFA) have also been associated with AMD [1,2].
Etiology and pathogenesis of AMD remain unclear, even if many biological processes have been implicated in AMD pathogenesis such as senescence identified in the retinal pigment epithelium (RPE; the pigmented cell layer just outside the retina that nourishes retinal cells) with lipofuscin accumulation, choroidal ischemia, oxidative damage and inflammation. Attention has also recently been focused on the Vascular Endothelial Growth Factor (VEGF) due to its role as a therapeutic target. The first clinical and pathological manifestations of AMD are thickening and loss of normal architecture in the Bruch's membrane (the innermost layer of the choroid, the vascular layer involved in the supply of nutrients to the retina), lipofuscin accumulation in RPE and increased number of large drusen. Drusen are extracellular deposits that accumulate inside the Bruch's membrane and below the RPE. They are composed of cellular remnants and debris derived from degenerate RPE cells, and proteins such as glycoproteins, lipids, apoliproproteins B and E, factor X, amyloid P component, amyloid β, immunoglobulins and inflammation-related proteins (including proteins of the complement system such as C5 and C5b-9 terminal complexes), as well as complement regulators (vitronectin and clusterin). Their precise role in the pathogenesis of AMD remains unclear; but it has been a long time since they are recognized as AMD hallmark [1].
Presence of many soft drusen (large and poorly demarcated) in the macula characterizes early AMD, together with RPE pigmentation impairment. Early AMD is associated with an important risk of progression to late AMD, where visual impairment happens. Late AMD occurs in two different forms, the wet (⅓ of patients) and the dry forms (⅔ of patients). In the wet or neovascular AMD form, loss of vision is a consequence of abnormal blood vessel growth (choroidal neovascularization) in the capillaries layer of the choroid. This process ultimately leads to bleeding, protein leaking, and scarring from these blood vessels below the macula and finally causes irreversible damage to the photoreceptors and rapid vision loss if left untreated. The dry form, or geographic atrophy, is characterized by the cell loss of RPE that manifests by oval areas of hypopigmentation. This process leads to photoreceptors degeneration since RPE cells are involved in their sustaining Retina becomes thinner, resulting in a progressive impairment of vision [1].
Until recently, laser treatment (photocoagulation) was the only approved treatment of wet AMD. This technique aims at ablating new choroidal blood vessels associated with little damages to surrounding retinal tissue. The long-term severe visual loss is efficiently reduced, but there is no gain of vision, as well as a high recurrence rate (50%) and a 41% risk of developing an immediate moderate visual loss. Improvement occurred with the use of photosensitizing agents such as verteporfin delivered intravenously just before laser treatment that accumulate preferentially in neovascular membranes [3]. Despite encouraging results these therapeutic options are much less used because they target only end-stage of the disease and do not act on its progression.
Anti-VEGF drugs are now the standard of care of the choroidal neovascularization pathogenesis. There are actually several VEGF inhibitors marketed for this indication: pegaptanib, ranibizumab, aflibercept, in addition to bevacizumab commonly used as an alternative off-label treatment. Use of these treatments is associated with significant visual stabilization and improvement. There are however two major issues: the need for a rigorous monthly administration, increasing the risk of complications such as endophthalmitis and the long-term safety issue of VEGF inhibitors that may potently enter the systemic circulation after ocular injection, especially bevacizumab and ranibizumab, leading to higher risk of vascular events. Much effort has focused on improvement of anti-VEGF treatments protocols in order to reduce the frequency of injections. As an example, the combination of anti-VEGF therapies together with photodynamic therapy and corticosteroids have been proposed, but recent results report insignificant improvements [4,5].
There is currently no treatment that stops or even slows down progression of the dry AMD. Many strategies are being tested in clinical trials. They aim at targeting either retinal toxins or complement or trophic factor supplementation or oxidative stress or inflammation.
There are obvious unmet medical needs concerning AMD treatments since non-fully satisfying treatments are available.